February 11th

Researchers at the Salk Institute have discovered a startling feature of early brain development that helps to explain how complex neuron wiring patterns are programmed using just a handful of critical genes. The findings, published in the February 3, 2012 issue of Cell, may help scientists develop new therapies for neurological disorders, such as amyotrophic lateral sclerosis (ALS), and provide insight into certain cancers. The Salk researchers discovered that only a few proteins on the leading edge of a motor neuron's axon - its outgoing electrical "wire" - and within the extracellular soup it travels through, guide the nerve as it emerges from the spinal cord. These molecules can attract or repel the axon, depending on the long and winding path it must take to finally connect with its target muscle. "The budding neuron has to detect the local environment it is growing through and decide where it is, and whether to grow straight, move to the left or right, or stop," says the study's senior investigator, Dr. Sam Pfaff, a professor in Salk's Gene Expression Laboratory and a Howard Hughes Medical Institute investigator. "It does this by mixing and matching just a handful of protein products to create complexes that tell a growing neuron which way to go, in the same way that a car uses the GPS signals it receives to guide it through an unfamiliar city," he says. The brain contains millions of times the number of neuron connections than the number of genes found in the DNA of brain cells. This is one of the first studies to try and understand how a growing neuron integrates many different pieces of information in order to navigate to its eventual target and make a functional connection.

February 10th

A new study shows that Kineret (anakinra), a medication approved for the treatment of rheumatoid arthritis, is effective in stopping the progression of organ damage in people with neonatal-onset multisystem inflammatory disease (NOMID). This rare and debilitating genetic disorder causes persistent inflammation and ongoing tissue damage. The research was performed by scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health. NOMID affects numerous organs and body systems, including the skin, joints, eyes, and central nervous system. The first sign of the disease is often a rash that develops within the first weeks of life. Other problems, including fever, meningitis, joint damage, vision and hearing loss, and mental retardation, can follow. Kineret, one of a relatively new class of drugs known as biologic response modifiers or biologics, blocks the activity of interleukin-1 (IL-1), a protein made by cells of the immune system. IL-1 is overproduced in NOMID and a number of other diseases, leading to damaging inflammation. Previous work by the same NIAMS group showed that blocking IL-1 was effective in relieving symptoms of NOMID. However, this is the first study to show that Kineret works over the long-term and, at higher doses, can also control damage that often results in vision and hearing loss, and brain lesions. “Inflammation prolonged over many years will eventually cause irreversible damage and loss of function,” said lead author Dr. Raphaela Goldbach-Mansky of the NIAMS Translational Autoinflammatory Disease Section. For example, inflammation of the cochlea — a tiny structure of the inner ear — was found to be responsible for hearing loss in people with NOMID.

There is a need to analyze tumor specimens at the time of ovarian cancer recurrence, according to a new study published in the February 2012 issue of Molecular Cancer Therapeutics. Researchers used a diagnostic technology called molecular profiling to examine the differences in the molecular characteristics of primary and recurrent ovarian tumors and found significant changes for some biomarkers. This is the first study that examined potential differences in a broad biomarker panel in patient-matched primary versus recurrent ovarian cancers and underscores the importance of analyzing the most current tumor tissue in order to make the most informed decisions about treatment for recurrence. Ovarian cancer is the most deadly of gynecological cancers, and is the fifth leading cause of cancer-related death among women in the United States. Treatment for recurrent ovarian cancer often follows a trial-and-error approach in spite of molecular profiling technologies available to inform treatment selection. Profiling technologies may be utilized at the time of ovarian cancer recurrence, but the tumor specimens that are analyzed are most often those obtained at initial diagnosis. This profiling of the primary tumor does not take into account changes that occur in recurrent tumors, which may have enabled their survival after chemotherapy treatment. Lead author Dr. Deb Zajchowski, Scientific Director of The Clearity Foundation, says, "These results highlight additional challenges for the treatment of recurrent ovarian cancer. The study helps us appreciate the degree to which tumor characteristics that may be useful for making treatment decisions may change over the course of this disease." Dr. Zajchowski, Clearity Scientific Advisor Dr. Beth Y.

Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer's disease. The researchers' findings, published online on February 9, 2012 in Science, show that use of a drug in mice appears to quickly reverse the pathological, cognitive, and memory deficits caused by the onset of Alzheimer's. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease. Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer's disease, and the results were more than promising. Alzheimer's disease arises in large part from the body's inability to clear naturally-occurring amyloid beta from the brain. In 2008, Case Western Reserve researcher Dr. Gary Landreth, professor of neurosciences, discovered that the main cholesterol carrier in the brain, apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. Dr. Landreth is the senior author of this Science study. Dr. Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced. In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer's disease.

February 9th

Scientists from the Florida campus of The Scripps Research Institute have identified a single prion protein that causes neuronal death similar to that seen in “mad cow” disease, but which is at least 10 times more lethal than larger prion species. This toxic single molecule or “monomer” challenges the prevailing concept that neuronal damage is linked to the toxicity of prion protein aggregates called “oligomers.” The study was published online on February 7, 2012 in PNAS. “By identifying a single molecule as the most toxic species of prion proteins, we’ve opened a new chapter in understanding how prion-induced neurodegeneration occurs,” said Scripps Florida Professor Corinne Lasmézas, who led the new study. “We didn’t think we would find neuronal death from this toxic monomer so close to what normally happens in the disease state. Now we have a powerful tool to explore the mechanisms of neurodegeneration.” In the study, the newly identified toxic form of abnormal prion protein, known as TPrP, caused several forms of neuronal damage ranging from apoptosis (programmed cell death) to autophagy, the self-eating of cellular components, as well as molecular signatures remarkably similar to that observed in the brains of prion-infected animals. The study found the most toxic form of prion protein was a specific structure described as alpha-helical. In addition to the insights it offers into prion diseases such as “mad cow” and a rare human form called Creutzfeldt-Jakob disease, the study opens the possibility that similar neurotoxic proteins might be involved in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In prion disease, infectious prions (short for proteinaceous infectious particles), thought to be composed solely of protein, have the ability to reproduce, despite the fact that they lack DNA and RNA.

February 6th

DNA sequencing to detect genetic mutations can aid in the diagnosis and selection of treatment for cancer. Current methods of testing DNA samples, specifically, Sanger sequencing and pyrosequencing, occasionally produce complex results that can be difficult or impossible to interpret. Scientists at the Johns Hopkins University School of Medicine have developed a free software program, Pyromaker, that can more accurately identify such complex genetic mutations. Pyromaker is a web-based application that produces simulated pyrograms based on user input, including the percentage of tumor and normal cells, the wild-type sequence, the dispensation order, and any number of mutant sequences. Pyromaker calculates the relative mutant and wild-type allele percentages and then uses these to generate the expected signal at each point in the dispensation sequence. The final result is a virtual trace of the expected pyrogram. The researchers validated Pyromaker against actual pyrograms containing common mutations in the KRAS gene, which plays an important role in the pathogenesis of a variety of tumors. The actual pyrograms and virtual pyrograms were quantitatively identical for all mutations tested. They then demonstrated that all codon 12 and 13 single and complex mutations generate unique pyrograms. However, some complex mutations were indistinguishable from single base mutations, indicating that complex mutations may be underreported.

February 5th

A genetic variant that increases the risk of a common type of stroke has been identified by scientists in a study published online in Nature Genetics on February 5, 2012. This is one of the few genetic variants to date to be associated with risk of stroke and the discovery opens up new possibilities for treatment. Stroke is the second leading cause of death worldwide (more than one in ten of all deaths, and over six million deaths annually), and also in developed countries is a major cause of chronic disability. As the world's populations age, the impact of stroke on wellbeing is likely to increase further. Several different mechanisms underlie strokes. One of the most common types is when blood flow is impaired because of a blockage to one or more of the large arteries supplying blood to the brain – large artery ischemic stroke. This accounts for over a third of all strokes. Researchers from St George's, University of London and Oxford University, working with scientists from Europe, America, and Australia, in one of the largest genetic studies of stroke to date, compared the genetic make-ups of 10,000 people who had suffered from a stroke with those of 40,000 healthy individuals. The study was funded by the Wellcome Trust. The researchers discovered an alteration in a gene called HDAC9 which affects a person's risk of large artery ischemic stroke. This variant occurs on about 10 per cent of human chromosomes. Those people who carry two copies of the variant (one inherited from each parent) have nearly twice the risk for this type of stroke compared to those with no copies of the variant. The protein produced by HDAC9 is already known to play a role in the formation of muscle tissue and heart development. However, the exact mechanism by which the genetic variant increases the risk of stroke is not yet known.

Henry Ford Hospital researchers in Detroit, Michigan, together with collaborators, have identified for the first time two molecules that together hold promise as a biomarker for measuring cartilage damage associated with osteoarthritis. Researchers say the concentrations of two molecules called non-coding RNAs in blood were associated with mild cartilage damage in 30 patients who were one year removed from reconstruction surgery to repair an anterior cruciate ligament, or ACL, injury. The findings are described as significant in the ongoing and tedious search for biomarkers for osteoarthritis, the most common form of arthritis that afflicts an estimated 27 million Americans aged 25 and older. It is caused by the normal aging process or wear and tear of a joint. The study was presented February 4, 2012 at the annual Orthopaedic Research Society conference in San Francisco. "Our results suggest we have identified a long-awaited biomarker for this leading cause of disability," says Dr. Gary Gibson, director of Henry Ford's Bone and Joint Center and the study's lead author. "For various pathology reasons associated with the variability of the disease and challenging blood biochemistry, developing a biomarker for osteoarthritis has been very elusive. But we believe our work shows great promise. The next step is to expand the number of patients studied and determine whether the degree in blood concentration can determine if the cartilage damage will worsen over time. Our ultimate goal is to develop a biomarker that can be used in the development of future treatments to prevent the progression of the disease," he added. The study, a collaboration of Henry Ford, the University of Guelph in Ontario, and University of Toronto, involved 121 Canadian patients from 2006-2011.

For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain's executive hub. Among key findings of the study by National Institutes of Health (NIH) scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain's prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth. Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make –what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan. "Developmental brain disorders may be traceable to altered methylation of genes early in life," explained Dr. Barbara Lipska, a scientist in the NIH's National Institute of Mental Health (NIMH) and lead author of the study. "For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory, and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability.

February 4th

One of the big mysteries in biology is why cells age. Now scientists at the Salk Institute for Biological Studies report that they have discovered a weakness in a component of brain cells that may explain how the aging process occurs in the brain. The scientists discovered that certain proteins, called extremely long-lived proteins (ELLPs), which are found on the surface of the nucleus of neurons, have a remarkably long lifespan. While the lifespan of most proteins totals two days or less, the Salk Institute researchers identified ELLPs in the rat brain that were as old as the organism, a finding they reported on February 2, 2012 in Science. The Salk scientists are the first to discover an essential intracellular machine whose components include proteins of this age. Their results suggest the proteins can last an entire lifetime, without being replaced. ELLPs make up the transport channels on the surface of the nucleus; gates that control what materials enter and exit. Their long lifespan might be an advantage if not for the wear-and-tear that these proteins experience over time. Unlike other proteins in the body, ELLPs are not replaced when they incur aberrant chemical modifications and other damage. Damage to the ELLPs weakens the ability of the three-dimensional transport channels that are composed of these proteins to safeguard the cell's nucleus from toxins, says Dr. Martin Hetzer, a professor in Salk's Molecular and Cell Biology Laboratory, who headed the research. These toxins may alter the cell's DNA and thereby the activity of genes, resulting in cellular aging. Funded by the Ellison Medical Foundation and the Glenn Foundation for Medical Research, Dr. Hetzer's research group is the only lab in the world that is investigating the role of these transport channels, called the nuclear pore complex (NPC), in the aging process.